Prior infection with unrelated neurotropic virus exacerbates influenza disease and impairs lung T cell responses

Isabelle Jia-Hui Foo, Brendon Y. Chua, E. Bridie Clemens, So Young Chang, Xiaoxiao Jia, Hayley A. McQuilten, Ashley Huey Yiing Yap, Aira F. Cabug, Mitra Ashayeripanah, Hamish E. G. McWilliam, Jose A. Villadangos, Maximilien Evrard, Laura K. Mackay, Linda M. Wakim, John K. Fazakerley, Katherine Kedzierska () and Lukasz Kedzierski ()
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Isabelle Jia-Hui Foo: The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Brendon Y. Chua: The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
E. Bridie Clemens: The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
So Young Chang: The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Xiaoxiao Jia: The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Hayley A. McQuilten: The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Ashley Huey Yiing Yap: The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Aira F. Cabug: The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Mitra Ashayeripanah: The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Hamish E. G. McWilliam: The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Jose A. Villadangos: The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Maximilien Evrard: The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Laura K. Mackay: The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Linda M. Wakim: The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
John K. Fazakerley: The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Katherine Kedzierska: The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Lukasz Kedzierski: The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Immunity to infectious diseases is predominantly studied by measuring immune responses towards a single pathogen, although co-infections are common. In-depth mechanisms on how co-infections impact anti-viral immunity are lacking, but are highly relevant to treatment and prevention. We established a mouse model of co-infection with unrelated viruses, influenza A (IAV) and Semliki Forest virus (SFV), causing disease in different organ systems. SFV infection eight days before IAV infection results in prolonged IAV replication, elevated cytokine/chemokine levels and exacerbated lung pathology. This is associated with impaired lung IAV-specific CD8+ T cell responses, stemming from suboptimal CD8+ T cell activation and proliferation in draining lymph nodes, and dendritic cell paralysis. Prior SFV infection leads to increased blood brain barrier permeability and presence of IAV RNA in brain, associated with increased trafficking of IAV-specific CD8+ T cells and establishment of long-term tissue-resident memory. Relative to lung IAV-specific CD8+ T cells, brain memory IAV-specific CD8+ T cells have increased TCR repertoire diversity within immunodominant DbNP366+CD8+ and DbPA224+CD8+ responses, featuring suboptimal TCR clonotypes. Overall, our study demonstrates that infection with an unrelated neurotropic virus perturbs IAV-specific immune responses and exacerbates IAV disease. Our work provides key insights into therapy and vaccine regimens directed against unrelated pathogens.

Date: 2024
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DOI: 10.1038/s41467-024-46822-7

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